Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

OBJECTIVES: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. METHODS: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. RESULTS: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. INTERPRETATION: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054.

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Cardioembolism after thoracoscopic left atrial appendage clipping in a patient on oral anticoagulation therapy.

Cardioembolism associated with atrial fibrillation is a major cause of ischemic stroke. Left atrial appendage occlusion in atrial fibrillation patients undergoing cardiac surgery reduces the risk of postoperative stroke. A 78-year-old man with a history of atrial fibrillation and severe mitral regurgitation underwent thoracoscopic mitral valve repair with left atrial appendage clipping and the cryo-maze procedure 4 years previously. He was taking a direct oral anticoagulant for stroke prevention because his atrial fibrillation had recurred. He presented with acute onset disturbed consciousness, omnidirectional gaze palsy, left facial palsy, severe dysarthria, bilateral limb ataxia, and sensory disturbance. National Institutes of Health Stroke Scale score was 16. Although non-contrast computed tomography showed no early ischemic changes, computed tomography angiography revealed occlusion of the basilar artery. Intravenous thrombolysis was performed, which resulted in recanalization. Transesophageal echocardiography showed left atrial spontaneous echo contrast and thrombus in the left atrial appendage. Contrast-enhanced chest computed tomography confirmed incomplete left atrial appendage occlusion. Cardioembolic stroke was diagnosed, and warfarin was initiated. Cardioembolism may occur after thoracoscopic left atrial appendage clipping despite direct oral anticoagulant therapy, particularly if appendage occlusion is incomplete. Occlusion status should be evaluated after thoracoscopic clipping. Learning objective: To illustrate, incomplete left atrial appendage closure may increase the risk of ischemic stroke even after thoracoscopic left atrial appendage clipping is performed to prevent embolism.

High pillow and spontaneous vertebral artery dissection: A case-control study implicating "Shogun pillow syndrome".

INTRODUCTION: The underlying causes of spontaneous vertebral artery dissection (sVAD) remain insufficiently understood. This study aimed to determine whether high-pillow usage is associated with an increased risk of sVAD and evaluate the frequency of sVAD attributable to high-pillow usage. PATIENTS AND METHODS: This case-control study identified patients with sVAD and age- and sex-matched non-sVAD controls (case-to-control ratio: 1:1) treated at a certified comprehensive stroke center in Japan between 2018 and 2023. The pillow height used at the onset of the index disease was measured and classified into three categories between 12 and 15 cm boundaries. Univariable logistic regression was performed to assess the odds ratio (OR) with a 95% confidence interval (CI) of high-pillow usage for sVAD development. A subgroup of sVAD attributable to high-pillow usage was defined with the following three conditions: high-pillow usage (⩾12 or ⩾15 cm); no minor preceding trauma; and wake-up onset. RESULTS: Fifty-three patients with sVAD and 53 non-sVAD controls (42% women, median age: 49 years) were identified. High-pillow usage (⩾12 and ⩾15 cm) was more common in the sVAD group than in the non-sVAD group (34 vs 15%; OR = 2.89; 95%CI = 1.13-7.43 and 17 vs 1.9%; OR = 10.6; 95%CI = 1.30-87.3, respectively). The subgroup of sVAD attributed to high-pillow usage (⩾12 and ⩾15 cm) was found in 11.3% (95%CI = 2.7%-19.8%) and 9.4% (95%CI = 1.5%-17.3%), respectively. CONCLUSION: High-pillow usage was associated with an increased risk of sVAD and accounted for approximately 10% of all sVAD cases. This tentative subgroup of sVAD may represent a distinct spectrum of disease-Shogun pillow syndrome.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Periodic discharges plus fast activity on electroencephalogram predict worse outcomes in poststroke epilepsy.

OBJECTIVE: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. METHODS: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short-term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short-term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long-term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. RESULTS: In this study, 307 patients with PSE (median age = 75 years, range = 35-97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short-term functional decline (12 [20%] vs. 8 [3.2%], p < .001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44-12.6, p = .009). Patients with superimposed fast-activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p = .003), prolonged hyperperfusion (100% vs. 62%, p = .023), and a significantly higher risk of short-term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87-259.4, p = .014). Six months after discharge, PDs+F were significantly associated with long-term functional decline (adjusted OR = 4.21, 95% CI = 1.27-13.88, p = .018). SIGNIFICANCE: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short- and long-term functional decline.

A Noonan-like pediatric patient with a de novo CBL pathogenic variant and an RNF213 polymorphism p.R4810K presenting with cardiopulmonary arrest due to left main coronary artery ostial atresia.

Left main coronary artery ostial atresia (LMCAOA) is an extremely rare condition. Here, we report the case of a 14-year-old boy with Noonan syndrome-like disorder in whom LMCAOA was detected following cardiopulmonary arrest. The patient had been diagnosed with Noonan syndrome-like disorder with a pathogenic splice site variant of CBL c.1228-2 A > G. He suddenly collapsed when he was running. After administering two electric shocks using an automated external defibrillator, the patient's heartbeat resumed. Cardiac catheterization confirmed the diagnosis of LMCAOA. Left main coronary artery angioplasty was performed. The patient was discharged without neurological sequelae. Brain magnetic resonance imaging revealed asymptomatic Moyamoya disease. In addition, RNF213 c.14429 G > A p.R4810K was identified. There are no reports on congenital coronary malformations of compound variations of RNF213 and CBL. In contrast, the RNF213 p.R4810K polymorphism has been established as a risk factor for angina pectoris and myocardial infarction in adults, and several congenital coronary malformations due to genetic abnormalities within the RAS/MAPK signaling pathway have been reported. This report aims to highlight the risk of sudden death in patients with RASopathy and RNF213 p.R4810K polymorphism and emphasize the significance of actively searching for coronary artery morphological abnormalities in these patients.

Tmax Mismatch Ratio to Identify Intracranial Atherosclerotic Stenosis-Related Large-Vessel Occlusion Before Endovascular Therapy.

Background We aimed to clarify which time-to-maximum of the tissue residue function (Tmax) mismatch ratio is useful in predicting anterior intracranial atherosclerotic stenosis (ICAS)-related large-vessel occlusion (LVO) before endovascular therapy. Methods and Results Patients with ischemic stroke who underwent perfusion-weighted imaging before endovascular therapy for anterior intracranial LVO were divided into those with ICAS-related LVO and those with embolic LVO. Tmax ratios of >10 s/>8 s, >10 s/>6 s, >10 s/>4 s, >8 s/>6 s, >8 s/>4 s, and >6 s/>4 s were considered Tmax mismatch ratios. Binominal logistic regression was used to identify ICAS-related LVO, and the adjusted odds ratio (aOR) and 95% CI for each Tmax mismatch ratio increase of 0.1 were calculated. A similar analysis was performed for ICAS-related LVO with and without embolic sources, using embolic LVO as the reference. Of 213 patients (90 women [42.0%]; median age, 79 years), 39 (18.3%) had ICAS-related LVO. The aOR (95% CI) per 0.1 increase in Tmax mismatch ratio in ICAS-related LVO with embolic LVO as reference was lowest with Tmax mismatch ratio >10 s/>6 s (0.56 [0.43-0.73]). Multinomial logistic regression analysis also showed the lowest aOR (95% CI) per 0.1 increase in Tmax mismatch ratio with Tmax >10 s/>6 s (ICAS-related LVO without embolic source: 0.60 [0.42-0.85]; ICAS-related LVO with embolic source: 0.55 [0.38-0.79]). Conclusions A Tmax mismatch ratio of >10 s/>6 s was the optimal predictor of ICAS-related LVO compared with other Tmax profiles, with or without an embolic source before endovascular therapy. Registration clinicaltrials.gov. Identifier NCT02251665.

Harboring Cnm-expressing Streptococcus mutans in the oral cavity relates to both deep and lobar cerebral microbleeds.

BACKGROUND: Cerebral microbleeds (CMBs) influence long-term prognoses of stroke patients. Streptococcus mutans expressing the collagen-binding protein Cnm induces cerebrovascular inflammation, impairing blood brain barrier integrity and causing cerebral bleeding. Here, we examine the association of Cnm-positive S. mutans with CMBs. METHODS: Acute stroke patients were selected from a single-center registry database. Oral carriage of Cnm-positive or Cnm-negative S. mutans was determined using polymerase chain reaction assays. The associations of Cnm-positive S. mutans with CMB number and specifically the presence of >10 CMBs were examined using quasi-Poisson and logistic regression models, respectively. RESULTS: This study included 3154 stroke patients, of which 428 patients (median [interquartile range] age, 73.0 [63.0-81.0] years; 269 men [62.9%]) underwent oral bacterial examinations. In total, 326 patients harbored S. mutans. After excluding four patients without imaging data, we compared patients with Cnm-positive (n = 72) and Cnm-negative (n = 250) S. mutans. Harboring Cnm-positive S. mutans was independently associated with the presence of >10 CMBs (adjusted odds ratio 2.20 [1.18-4.10]) and higher numbers of deep and lobar CMBs (adjusted risk ratio 1.61 [1.14-2.27] for deep; 5.14 [2.78-9.51] for lobar), but not infratentorial CMBs, after adjusting for age, sex, hypertension, stroke type, National Institutes of Health Stroke Scale score, and cerebral amyloid angiopathy. CONCLUSIONS: Harboring Cnm-positive S. mutans was independently associated with a higher number of CMBs in deep and lobar locations. Reducing Cnm-positive S. mutans in the oral cavity may serve as a novel therapeutic approach for stroke.

Plasma mid-regional pro-adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke.

Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n = 119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5 h of onset. MR-proADM levels in HAIS were compared to healthy controls (n = 1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (rs  = 0.09, p = 0.348), they were higher in HAIS with CDM (n = 34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n = 26; 0.83 vs. 0.62 nmol/L, p = 0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4.65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.

Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

OBJECTIVE: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. METHODS: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. RESULTS: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data). INTERPRETATION: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370.

Detrimental effect of anemia after mechanical thrombectomy on functional outcome in patients with ischemic stroke.

Background: Anemia can occur due to an aspiration maneuver of blood with thrombi during mechanical thrombectomy (MT) for stroke. However, the association between postoperative anemia and stroke outcomes is unknown. Methods: In a registry-based hospital cohort, consecutive patients with acute ischemic stroke who underwent MT were retrospectively recruited. Patients were divided into the following three groups according to their hemoglobin (Hb) concentrations within 24 h after MT; no anemia (Hb concentrations ≥13 g/dL for men and ≥ 12 g/dL for women), mild anemia (Hb concentrations of 11-13 g/dL and 10-12 g/dL, respectively), and moderate-to-severe anemia (Hb concentrations <11 g/dL and < 10 g/dL, respectively). A 3-month modified Rankin Scale score of 0-2 indicated a favorable outcome. Results: Of 470 patients, 166 were classified into the no anemia group, 168 into the mild anemia group, and 136 into the moderate-to-severe anemia group. Patients in the moderate-to-severe anemia group were older and more commonly had congestive heart failure than those in the other groups. Patients in the moderate-to-severe anemia group also had more device passes than those in the other groups (p < 0.001). However, no difference was observed in the rate of final extended thrombolysis in cerebral infarction ≥2b reperfusion or intracranial hemorrhage among the groups. A favorable outcome was less frequently achieved in the moderate-to-severe anemia group than in the no anemia group (adjusted odds ratio, 0.46; 95% confidence interval, 0.26-0.81) independent of the baseline Hb concentration. A restricted cubic spline model with three knots showed that the adjusted odds ratio for a favorable outcome was lower in patients with lower Hb concentrations within 24 h after MT. Conclusion: Moderate-to-severe anemia within 24 h after MT is independently associated with a reduced likelihood of a favorable outcome. Clinical trial registration: https://www.clinicaltrials.gov, NCT02251665.

Interictal epileptiform discharges as a predictive biomarker for recurrence of poststroke epilepsy.

Poststroke epilepsy is a major ischaemic/haemorrhagic stroke complication. Seizure recurrence risk estimation and early therapeutic intervention are critical, given the association of poststroke epilepsy with worse functional outcomes, quality of life and greater mortality. Several studies have reported risk factors for seizure recurrence; however, in poststroke epilepsy, the role of EEG in predicting the risk of seizures remains unclear. This multicentre observational study aimed to clarify whether EEG findings constitute a risk factor for seizure recurrence in patients with poststroke epilepsy. Patients with poststroke epilepsy were recruited from the PROgnosis of POst-Stroke Epilepsy study, an observational multicentre cohort study. The enrolled patients with poststroke epilepsy were those admitted at selected hospitals between November 2014 and June 2017. All patients underwent EEG during the interictal period during admission to each hospital and were monitored for seizure recurrence over 1 year. Board-certified neurologists or epileptologists evaluated all EEG findings. We investigated the relationship between EEG findings and seizure recurrence. Among 187 patients with poststroke epilepsy (65 were women with a median age of 75 years) admitted to the lead hospital, 48 (25.7%) had interictal epileptiform discharges on EEG. During the follow-up period (median, 397 days; interquartile range, 337-450 days), interictal epileptiform discharges were positively correlated with seizure recurrence (hazard ratio, 3.82; 95% confidence interval, 2.09-6.97; P < 0.01). The correlation remained significant even after adjusting for age, sex, severity of stroke, type of stroke and generation of antiseizure medications. We detected periodic discharges in 39 patients (20.9%), and spiky/sharp periodic discharges were marginally associated with seizure recurrence (hazard ratio, 1.85; 95% confidence interval, 0.93-3.69; P = 0.08). Analysis of a validation cohort comprising 187 patients with poststroke epilepsy from seven other hospitals corroborated the association between interictal epileptiform discharges and seizure recurrence. We verified that interictal epileptiform discharges are a risk factor for seizure recurrence in patients with poststroke epilepsy. Routine EEG may facilitate the estimation of seizure recurrence risk and the development of therapeutic regimens for poststroke epilepsy.

Effects of Jaw-Opening Exercises with/without Pain for Temporomandibular Disorders: A Pilot Randomized Controlled Trial.

This study aimed to evaluate the effects of jaw-opening exercises with and without pain on temporomandibular disorders (TMDs), specifically in relation to pain intensity and range-of-mouth opening in patients with TMDs. Participants were randomly assigned to either the jaw-opening exercise with pain (JE w/pain) or the jaw-opening exercise without pain (JE w/o pain) groups, and each exercise was performed for eight weeks. TMDs pain intensity was assessed using a 100-mm visual analog scale (VAS), and the range-of-mouth opening was evaluated at the baseline (T0), 2 weeks (T1), 4 weeks (T2), and 8 weeks (T3). Of the 61 participants, 57 (JE w/pain group, n = 30; JE w/o pain group, n = 27) were included in the analysis. The range-of-mouth opening and TMDs pain intensity improved from T1 to T3 in both groups. The JE w/pain group showed significant differences at T3 compared to T1 (pain-free unassisted mouth opening, p = 0.006; jaw-opening pain, p = 0.014; chewing pain, p = 0.018). In addition, the JE w/pain group showed significantly greater changes in the maximum unassisted mouth opening at T2 and T3 than the JE w/o pain group (T2, p < 0.001; T3, p = 0.003). Thus, jaw-opening exercises, until the occurrence of pain, may be effective in patients with TMDs.

Case report: Near-complete cortical hearing loss caused by sequential development of bilateral putaminal hemorrhage.

Intracerebral hemorrhage with sudden hearing loss as the initial symptom is rare. A right-handed man with a history of right putaminal hemorrhage developed near-complete hearing loss and right hemiplegia and was taken to our hospital by ambulance. Non-contrast computed tomography demonstrated acute intracerebral hemorrhage in the left putamen. A region of old right putaminal hemorrhage involving the right temporal stem was also shown on fluid-attenuated inversion recovery. Standard pure-tone audiometry showed right-dominant bilateral sensorineural hearing loss. More than 2 months after onset, the bilateral sensorineural hearing loss gradually improved without interfering with daily life. Detailed history-taking indicated that the old hemorrhage in the right putamen 12 years previously had caused sudden left-dominant bilateral hearing impairment due to asymmetric but bilateral innervation from the auditory nerve. The bilateral damage to the temporal stem involving acoustic radiation resulted in temporary near-complete hearing loss after the recurrence, but the amelioration of edema in the left temporal stem may have resulted in partial recovery of the hearing loss. This patient's clinical progression suggests that the auditory tract ascends mainly on the side opposite the ear and may explain the left dominance in the level of acoustic radiation.

Effect of Different Maxillary Oral Appliance Designs on Respiratory Variables during Sleep.

This study aimed to analyze the efficacy of maxillary oral appliance (MOA) designs on respiratory variables during sleep. At baseline, 23 participants underwent a sleep test with a portable device for two nights and were categorized as participants with mild obstructive sleep apnea (mild-OSA) (n = 13) and without OSA (w/o-OSA) (n = 10). Three types of MOAs, standard-OA (S-OA), palatal covering-OA (PC-OA), and vertically increasing-OA (VI-OA), were each worn for three nights, and sleep tests with each MOA were performed with a portable device for two nights. Based on the average of the respiratory event index (REI) values for the two nights for each MOA, w/o-OSA participants with an REI ≥ 5.0 were defined as the exacerbation group and those with an REI < 5.0 as the non-exacerbation group. In mild-OSA participants, an REI ≥ 15.0 or REI ≥ baseline REI × 1.5 were defined as the exacerbation group and those with an REI < 15.0 and REI < baseline REI × 1.5 were defined as the non-exacerbation group. The percentage of the exacerbation and non-exacerbation groups with MOA was evaluated in the w/o-OSA and mild-OSA participants. The maxillary and mandibular dental-arch dimension was compared by dentition model analysis. The exacerbation group in w/o-OSA participants (n = 10) comprised 10.0% participants (n = 1) with S-OA, 40.0% (n = 4) with PC-OA, and 30.0% (n = 3) with VI-OA. The exacerbation group in the mild-OSA participants (n = 13) comprised 15.4% subjects (n = 2) with S-OA, 23.1% (n = 3) with PC-OA, and 23.1% (n = 3) in VI-OA. In the model analysis for w/o-OSA, the posterior dental arch width was significantly greater in the exacerbation group than in the non-exacerbation group wearing S-OA (p < 0.05). In addition, the ratio of the maxillary to mandibular dental arch width (anterior dental arch width) was significantly greater in the exacerbation group than in the non-exacerbation group for both PC-OA and VI-OA (p < 0.05). In mild-OSA, the maxillary and mandibular dental arch lengths and the ratio of maxillary to mandibular dental arch width (posterior dental arch width) were significantly smaller in the exacerbation group than in the non-exacerbation group for S-OA (p < 0.05). This study confirmed that wearing an MOA by w/o-OSA and mild-OSA participants may increase the REI during sleep and that PC-OA and VI-OA may increase the REI more than S-OA. The maxillary and mandibular dental-arch dimensions may affect the REI when using an MOA.

Moyamoya disease: diagnosis and interventions.

Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.